Dimethyl fumarate protects the aged brain following chronic cerebral hypoperfusion-related ischemia in rats in Nrf2-dependent manner

Shavakandi, Seyyedeh-Mahla; Ranjbaran, Mina; Nabavizadeh, Fatemeh; Vali, Reyhaneh; Sehati, Fardin; Ashabi, Ghorbangol

doi:10.1080/1028415x.2021.1940429

Cited by 6 publications

(2 citation statements)

References 49 publications

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“…These changes are comparable to the ∼2X increase in total NRF2 observed in the aged rat hippocampus following treatment with DMF, an FDA-approved pharmacologic NRF2 activator. 36,67,68 Moreover, one of the physiological effects of DR, intermittent hypoxia alone, induces a substantial increase in total NRF2 (∼3X) in an in vitro blood-brain barrier model. 11 This finding aligns with the observed increase in phosphorylated NRF2 in the hippocampus by ADR (2–4X).…”

Section: Discussionmentioning

confidence: 99%

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

Powell,

Wadolowski,

Tambo

et al. 2024

Preprint

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Aims: This study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses. Methods: Male Sprague-Dawley rats (n=38) underwent either a single diving session to elicit acute diving reflex, or daily diving sessions for 4-weeks to produce chronic diving reflex. NRF2 (total, nuclear, phosphorylated), NRF2-downstream genes, and malondialdehyde were assessed via Western blot, immunofluorescence, RT-PCR, and ELISA in brain, lung, kidney, and serum. Results: Diving reflex increased nuclear NRF2, phosphorylated NRF2, and antioxidative gene expression, in an organ-specific and exposure time-specific manner. Comparing organs, the brain had the highest increase of phosphorylated NRF2 expression, while kidney had the highest degree of nuclear NRF2 expression. Comparing acute and chronic sessions, phosphorylated NRF2 increased the most with chronic diving reflex, but acute diving reflex had the highest antioxidative gene expression. Notably, calcitonin gene-related peptide appears to mediate diving reflex' effects on NRF2 activation. Conclusions: Acute and chronic diving reflex activate potent NRF2 signaling in the brain and peripheral organs. Interestingly, acute diving reflex induces higher expression of downstream antioxidative genes compared to chronic diving reflex. This result contradicts previous assumptions requiring chronic exposure to diving for induction of antioxidative effects and implies that the diving reflex has a strong translational potential during preconditioning and postconditioning therapies.

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Section: Discussionmentioning

confidence: 99%

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

Powell,

Wadolowski,

Tambo

et al. 2024

Preprint

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show abstract

“…This is in line with a previous studies demonstrating with various models of cerebral ischemia that pharmacological activation of Nrf2 exerts protective effects. This includes sulforaphane, which will be discussed below, as well as other Nrf2 activators, including dimethyl fumarate [64,65], tert-butylhydroquinone [66,67], metformin [68,69], resveratrol [70,71], and many others [72].…”

Section: Nrf2 As a Promising Therapeutic Target Against Cerebral Isch...mentioning

confidence: 99%

Is Nrf2 Behind Endogenous Neuroprotection of the Hippocampal CA2-4,DG Region?

2022

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The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is the master regulator of genes known to be involved in antioxidant, and anti-inflammatory processes, metabolic regulation, and other cellular functions. Here, we also hypothesize a core role for it in endogenous neuroprotection, i.e., the natural adaptive mechanisms protecting the brain from ischemia–reperfusion (I/R) episode. An example of endogenous neuroprotection is ischemia-resistance of the hippocampal regions comprising the CA2, CA3, CA4 and dentate gyrus subfields (here abbreviated to CA2-4,DG) which can be contrasted with the ischemia-vulnerable CA1 region. In the work detailed here, we used a gerbil model of transient cerebral ischemia to examined Nrf2 activation in CA1 and CA2-4,DG, in a control group, and post I/R episode. Data obtained indicate enhanced Nrf2 activity in CA2-4,DG as compared with CA1 in the control, with this difference seen to persist even after I/R. While I/R does indeed cause further activation of Nrf2 in CA2-4,DG, it is associated with slight and transient activation in CA1. Sub-regional differences in Nrf2 activity correlate with immunoreactivity of Keap1 (an Nrf2 suppressor) and Nrf2 target proteins, including heme oxygenase 1, the catalytic and modulatory sub-units of glutamate-cysteine ligase, and glutathione peroxidase 1. Pharmacological Nrf2 activation by sulforaphane results in protection of CA1 after I/R episode. Our results therefore suggest that high Nrf2 activity in CA2-4,DG may guarantee resistance of this region to I/R, potentially explaining the differential sensitivities of the hippocampal regions.

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Neuroprotective effects of dimethyl fumarate against manic-like behavior induced by ketamine in rats

Saljoughi

Kalantar

Azadnasab

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Dimethyl fumarate protects the aged brain following chronic cerebral hypoperfusion-related ischemia in rats in Nrf2-dependent manner

Cited by 6 publications

References 49 publications

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

Is Nrf2 Behind Endogenous Neuroprotection of the Hippocampal CA2-4,DG Region?

Neuroprotective effects of dimethyl fumarate against manic-like behavior induced by ketamine in rats

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